SUZANNE L. MANSOUR
Professor of Human Genetics
The Mansour lab
Neurobiology of Disease
The mouse inner ear and dysmorphogenesis in an Fgf3 mutant. (A) An E15.5 mouse embryo was cleared and its inner ear filled with latex paint (brightfield). (B) Normal inner ear morphogenesis at E15.5 (darkfield). (C) Abnormal inner ear morphogenesis at E15.5 in an Fgf3 null mutant (darkfield)
FGF signaling and ear development
The inner ear, which mediates our sensations of hearing and balance, is derived almost entirely from a small patch of head ectoderm (the otic placode), which is specified for an otic fate early in fetal development. Following a series of signaling interactions with nearby tissues, the otic ectoderm undergoes complex processes of morphogenesis and differentiation to arrive at its final functional form. Abnormalities at any stage can lead to congenital deafness, which is the most common human sensory disorder. To better understand these disorders, my laboratory employs genetic and molecular approaches to identify and characterize genes that are important for the development and/or function of the mouse inner ear.
Multiple fibroblast growth factors (FGFs) are expressed in dynamically changing patterns during ear development, and FGF signaling plays critical dosage-sensitive roles in this process. Disruption of either Fgf3 or Fgf10 alone leads to variable defects of mouse inner ear morphogenesis, whereas Fgf3/Fgf10 double mutants have no inner ear development at all, showing that these genes are required redundantly for the initial induction of the otic placode, as well as individually in subsequent morphogenetic steps. A similar phenotype is seen in Fgf3/Fgf8 double mutants, and this occurs because Fgf8 is upstream of Fgf10. We are now using conditional mouse mutants to dissect the tissue origins of these inductive FGF signals and to investigate combinatorial roles for FGFs during later morphogenesis. In addition, we compared control and FGF-deficient otic placodes via microarray analyses, identifying new targets of FGF signaling that constitute the "blueprint" directing ear development. Roles for such FGF target genes in both early and later stages of inner ear development are under investigation.
FGF signaling can also be modulated at the level of the receptor. The heterozygous Pro250Arg substitution mutation in FGFR3, which increases ligand-dependent signaling, is the most common genetic cause of craniosynostosis in humans and defines Muenke syndrome. Since FGF signaling plays dosage sensitive roles in the differentiation of the auditory sensory epithelium, we evaluated hearing in a large group of Muenke syndrome subjects, as well as in the corresponding mouse model (Fgfr3P244R). The Muenke syndrome cohort showed significant, but incompletely penetrant, predominantly low-frequency sensorineural hearing loss, and the Fgfr3P244R mice showed dominant, fully penetrant hearing loss that was more severe than that of Muenke syndrome individuals, but had the same pattern of relative high-frequency sparing. The mouse hearing loss correlated with an alteration in the fate of supporting cells along the entire length of the cochlear duct, with the most extreme abnormalities found at the apical or low-frequency end. Thus, low-frequency sensorineural hearing loss is a characteristic feature of Muenke syndrome, and the genetically equivalent mouse provides an excellent model that is being used to investigate the development of this syndrome and test hearing loss therapies aimed at manipulating the levels of FGF signaling in the inner ear.
Ohta, S., Mansour, S.L., and Schoenwolf, G.C. (2010) BMP/SMAD Signaling regulates the cell behaviors that drive the initial dorsal-specific regional morphogenesis of the otocyst. Dev. Biol., 347:369-381. Cover illustration.
Urness, L.D., Bleyl, S.B., Wright, T.J., Moon, A.M., and Mansour, S.L. (2011) Redundant and dosage sensitive requirements for Fgf3 and Fgf10 in cardiovascular development. Dev. Biol., in press.
Urness, L.D., Paxton, C., Wang, X., Schoenwolf, G.C., and Mansour, S.L. (2010) FGF signaling regulates otic placode induction and refinement by controlling both ectodermal target genes and hindbrain Wnt8a. Dev. Biol., 340:595-604.
Mansour, S.L., Twigg, S.R.F., Freeland, R.M., Wall, S.A., Li, C., and Wilkie, A.O.M. (2009) Hearing loss in a mouse model of Muenke syndrome. Hum. Mol. Genet., 18:43-50.
Hatch, H.A., Urness, L.D., and Mansour, S.L. (2009) Fgf16IRESCre mice: A tool to inactivate genes expressed in inner ear cristae and spiral prominence epithelium. Dev. Dyn., 238:358-366.
Urness, L.D., Li, C., Wang, X., and Mansour, S.L. (2008) Expression of ERK signaling inhibitors Dusp6, Dusp7 and Dusp9 during mouse ear development. Dev. Dyn., 237:163-169.
Hatch, E., Noyes, C.A., Wang, X., Wright, T.J., and Mansour, S.L. (2007) Fgf3 is required for dorsal patterning and morphogenesis of the inner ear. Development, 134:3615-3625.
Li, C., Scott, D.A., Hatch, E., Tian, X., and Mansour, S.L. (2007) Dusp6 is a negative feedback regulator of FGF stimulated ERK signaling during mouse development. Development, 134:167-176.
Mansour, S.L. and Schoenwolf, G.C. (2005) Morphogenesis of the inner ear. In: The Springer Handbook of Auditory Research. Vol. 26, Development of the Inner Ear. Kelley, M.W. Wu, D.K., Popper, A.N., Fay, R.R., eds. (Springer, New York), pp. 43-84.
Ladher, R.K., Wright, T.J., Moon, A.M., Mansour, S.L., and Schoenwolf, G.C. (2005) FGF8 initiates inner ear induction. Genes Dev., 19:603-613.
Wright, T.J., Ladher, R., McWhirter, J., Murre, C., Schoenwolf, G.C., and Mansour, S.L. (2004) Mouse FGF15 is the ortholog of human and chick FGF19, but is not uniquely required for otic induction. Dev. Biol., 269:264-275.
Wright, T.J., and Mansour, S.L. (2003) FGF signaling in ear development and innervation. Curr. Top. Dev. Biol., 57:225-59.
Wright, T.J., Hatch, E., Karabagli, P., Karabagli, H., Schoenwolf, G.C., and Mansour, S.L. (2003) Expression of mouse fibroblast growth factors and receptors during early inner ear development. Dev. Dyn., 228:267-272
Wright, T.J., and Mansour, S.L. (2003) Fgf3 and Fgf10 are required for mouse otic placode induction. Development, 130:3379-3390.
Yang, W., Li, C., and Mansour, S.L. (2001) Impaired motor coordination in mice that lack punc. Mol. Cell Biol., 21:6031-6043.
Yang, W., Li, C., Ward, D., Kaplan, J., and Mansour, S.L. (2000) Altered trafficking of organellar membrane proteins in Ap3b1-deficient cells. J. Cell Sci., 113:4077-4086.
Yang, W., Musci, T.S., and Mansour, S.L. (1997) Trapping genes expressed in the developing mouse inner ear. Hear. Res., 114:53-61.
Mansour, S.L., Goddard, J.M., and Capecchi, M.R. (1993) Mice homozygous for a targeted disruption of the proto-oncogene int-2 have developmental defects in the tail and inner ear. Development, 117:13-28.